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Establishment and characterization of a murine T-cell lymphoma/leukemia model
Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Department of Medical Biosciences.
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Mouse models of human disease are valuable tools for studying pathogenesis and for evaluating novel therapies. T-cell lymphoma is a relatively rare disease in humans, affecting 100-150 persons yearly in Sweden. It exists in both aggressive and more indolent forms. We have established a mouse model for an aggressive T-cell lymphoma, the T-cell lymphoma/leukemia (TLL) mouse. In the present thesis, the TLL mouse model was characterized and used for experimental therapeutic and primary prevention studies.

The TLL mouse was established unintentionally in our laboratory during work on VH-gene replacement in a “knock-in” mouse experimental setting. The generated chimeras all developed aggressive T-cell lymphomas affecting the lymphoid organs, lungs, kidneys and liver. The lymphoma phenotype segregated from the targeted locus and we could demonstrate the presence of Moloney murine leukemia virus (MMLV) in the germline of the affected mice. MMLV is a retrovirus known to induce T-cell lymphomas when inoculated in newborn mice.  We further characterized two TLL substrains; TLL-2 and TLL-14 carrying the proviral integrations on chromosomes 2 and 14 respectively. Significant differences were found between the substrains regarding lymphoma frequency and immunophenotype, the TLL-14 substrain developing tumors with higher frequency than TLL-2 and with a more mature immunophenotype.

A transfer model was developed in which TLL cells could be readily transferred intravenously to syngenic recipients causing aggressive lymphomas. The transfer model was used in a therapeutic study where the selective COX-2 inhibitor celecoxib was evaluated as a single agent and in combination with the established anti-tumor agent cyclophosphamide. The study was based on results from other tumor types that have indicated celecoxib, originally an anti-inflammatory and analgetic drug, to have possible anti-tumor effects. In our TLL model, however, we could not demonstrate any benefit of celecoxib monotherapy or any additive effect to cyclophosphamide.

Dietary fatty acids, in particular omega-3 fatty acids, have been a focus of public and scientific interest due to observed effects on the prevention of cardiovascular disease, cancer and inflammatory conditions. In addition, omega-3 fatty acids inhibit T-cell proliferation in vitro. We supplemented the diet of TLL mice with omega-3 and omega-6 fatty acids respectively and could demonstrate a significant delay in lymphoma onset between 5-8 months of age in the group receiving an omega-3 rich diet.

Place, publisher, year, edition, pages
Umeå: Umeå universitet , 2010. , 66 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1348
Keyword [en]
Mouse model, T-cell lymphoma, Moloney murine leukemia virus, proviral integration, lymphomagenesis, COX-2, omega 3
National Category
Cancer and Oncology
Research subject
Oncology
Identifiers
URN: urn:nbn:se:umu:diva-35195ISBN: 978-91-7264-992-7 (print)OAI: oai:DiVA.org:umu-35195DiVA: diva2:337750
Public defence
2010-10-01, Sal B, 9tr, by 1D, Norrlands universitetssjukhus, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2010-09-08 Created: 2010-08-09 Last updated: 2010-09-08Bibliographically approved
List of papers
1. Establishment and characterization of a mouse strain (TLL) that spontaneously develops T-cell lymphomas/leukemia
Open this publication in new window or tab >>Establishment and characterization of a mouse strain (TLL) that spontaneously develops T-cell lymphomas/leukemia
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1999 (English)In: Experimental Hematology, ISSN 0301-472X, E-ISSN 1873-2399, Vol. 27, no 4, 682-688 p.Article in journal (Refereed) Published
Abstract [en]

In this study, a mouse strain (TLL) that spontaneously develops T-cell lymphomas/leukemia with an early onset and high incidence was established and characterized. All tumors analyzed were found to express the alpha,beta T-cell receptor, and the majority of them had a mature, CD3+CD4+CD8- immunophenotype. In a few cases, tumors with a more immature CD3+CD4+CD8+ phenotype were isolated. Expanded phenotyping using a broad panel of lymphocyte differentiation markers confirmed the mature T-cell phenotype of the tumors. Histologic and cell cycle analysis of the tumors revealed an aggressive lymphoblastic malignancy with a very high proliferation rate and widespread engagement of bone marrow and lymphoid as well as nonlymphoid organs. Thus, the TLL mouse strain represents a unique model for the analysis of the oncogenesis and progression of mature T-cell tumors and for the development of therapeutic measures to combat such tumors.

Keyword
T-cell lymphoma, t-cell leukemia, cd3 antigen, cd4 antigen, cd8 antigen
National Category
Cancer and Oncology
Research subject
Oncology
Identifiers
urn:nbn:se:umu:diva-35017 (URN)10.1016/S0301-472X(99)00003-X (DOI)10210326 (PubMedID)
Available from: 2010-07-02 Created: 2010-07-02 Last updated: 2017-12-12Bibliographically approved
2. Germ line insertions of moloney murine leukemia virus in the TLL mouse causes site-specific differences in lymphoma/leukemia frequency and tumor immunophenotype
Open this publication in new window or tab >>Germ line insertions of moloney murine leukemia virus in the TLL mouse causes site-specific differences in lymphoma/leukemia frequency and tumor immunophenotype
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2006 (English)In: Anticancer Research, ISSN 0250-7005, Vol. 26, no 4B, 2873-2878 p.Article in journal (Refereed) Published
Abstract [en]

Background: Moloney murine leukemia virus (Mo-MLV) has proven valuable for studies of the pathogenesis of malignant lymphoma. Inoculation of newborn mice induces T cell lymphoma with 100% incidence. The TLL (T cell lymphoma/leukemia)-strain was previously established and was shown to spontaneously develop T cell lymphoma at high frequency.

Materials and Methods: Differential screening of cDNA libraries was performed to discover an involvement of Mo-MLV and genomic sequencing was used to identify the chromosomal position of Mo-MLV proviral integration sites. Immunophenotypes of the tumors were established by flow cytometry. Disease frequency curves were created according to the Kaplan-Meier method.

Results: Two independent Mo-MLV germ line integrations were characterized on chromosomes 2 and 14, giving rise to two substrains of mice denoted TLL-2 and TLL-14. The chromosomal position of the integrated provirus affected the frequency of disease, as well as the immunophenotype of the tumors.

Conclusion: The data suggest that factors influencing the transcriptional activity of the chromosomal regions, leading to differences in proviral expression, could underlie the observed difference in tumor frequency.

Keyword
Animals, CD4-Positive T-Lymphocytes/immunology, CD8-Positive T-Lymphocytes/immunology, Immunophenotyping, Leukemia; T-Cell/*genetics/immunology/*virology, Lymphoma; T-Cell/*genetics/immunology/*virology, Mice, Mice; Inbred C57BL, Moloney murine leukemia virus/*genetics, Virus Integration
National Category
Cancer and Oncology
Research subject
Oncology
Identifiers
urn:nbn:se:umu:diva-15295 (URN)16886607 (PubMedID)
Available from: 2008-01-11 Created: 2008-01-11 Last updated: 2010-09-08Bibliographically approved
3. Lymphoblastic T-cell lymphoma in mice is unaffected by Celecoxib as single agent or in combination with cyclophosphamide
Open this publication in new window or tab >>Lymphoblastic T-cell lymphoma in mice is unaffected by Celecoxib as single agent or in combination with cyclophosphamide
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2009 (English)In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 50, no 7, 1198-1203 p.Article in journal (Refereed) Published
Abstract [en]

Celecoxib, an inhibitor of cyclooxygenase-2, is a promising novel antitumor agent with pleitropic mechanisms of action. Whereas this drug induces growth arrest and apoptosis of B-lymphoma cells, its effect against aggressive T-cell neoplasms remains to be studied. We therefore evaluated Celecoxib therapy of immunocompetent mice transplanted with lymphoblastic T-cell lymphomas. Oral Celecoxib in clinically relevant and non-toxic doses did not affect the degree of hypersplenism or the number of viable lymphoma cells. The clinical deterioration of Celecoxib-treated mice was not different from untreated controls. The impact of adding Celecoxib (60 mg/kg) to cyclophosphamide (200 mg/kg x 1, i.p.) was assessed but showed no benefit compared to cyclophosphamide alone. Thus, Celecoxib lacks effect against lymphoblastic T-cell lymphoma in mice.

Keyword
T-cell lymphoma, mouse, prostaglandins, Celecoxib, chemotherapy
National Category
Cancer and Oncology
Research subject
Oncology
Identifiers
urn:nbn:se:umu:diva-35016 (URN)10.1080/10428190902946930 (DOI)19557641 (PubMedID)
Available from: 2010-07-02 Created: 2010-07-02 Last updated: 2017-12-12Bibliographically approved
4. Fish oil delays lymphoma progression in the TLL mouse
Open this publication in new window or tab >>Fish oil delays lymphoma progression in the TLL mouse
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(English)Manuscript (preprint) (Other academic)
National Category
Cancer and Oncology
Research subject
Oncology
Identifiers
urn:nbn:se:umu:diva-35036 (URN)
Available from: 2010-07-02 Created: 2010-07-02 Last updated: 2010-09-08Bibliographically approved

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Johansson, Ann-Sofie

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